2-substituted morpholine and thiomorpholine derivatives as GABA-B antagonists

ABSTRACT

Disclosed are compounds of the formula I wherein: 
     Y represents --CO 2  H, --CO 2  R 6 , --C(O)NHR 7 , --SO 2  H, --SO 3  H, --SO 3  R 6 , --SO 2  NHR 7 , --C(O)--N(OH)--R 8 , or a group of the formula ##STR1##  or a pharmaceutically acceptable addition salt or solvate thereof. Also disclosed are pharmaceutical compositions containing compounds of Formula I. Further disclosed is a method for treating or preventing respiratory depression, epileptic seizures or other central nervous system disorders, and for enhancing cognitive performance, by administering an effective amount of a compound of Formula I.

The present application is United States national applicationcorresponding to International Application No. PCT/US 94/02803, filedMar. 23, 1994 and designating the United States, which PCT applicationis in turn a continuation-in-part of U.S. application Ser. No.08/038,584, filed Mar. 26, 1993 abandoned on May 2, 1994 the benefit ofwhich applications are claimed pursuant to the provisions to the 35U.S.C. 120, 363 and 365 (C).

BACKGROUND OF THE INVENTION

The present invention relates to morpholine and thiomorpholinederivatives, pharmaceutical compositions, and methods of using suchderivatives.

It is well established that there are two classes of receptors for theneurotransmitter γ-aminobutyric acid (GABA), which have been identifiedas GABA_(A) and GABA_(B). Selective GABA_(B) agonists, such as(-)-baclofen, are known and have demonstrated clinical utility as musclerelaxants. Kerr, et al, in GABA_(B) Receptors in Mammalian Function,Bowery, et al, eds., pp. 29-45, (Chichester 1990), have reported lowaffinity GABA_(B) antagonists, such as phaclofen and 2-hydroxy saclofen.Olpe, et al, Eur. J. Pharmacol., 187, 27 (1990), discloses the GABA_(B)antagonist 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP 35348),which, although having a low receptor affinity (comparable to 2-hydroxysaclofen), can penetrate the blood/brain barrier. In addition, Hills, etal, Br. J. Pharmacol., 102, pp. 5-6 (1991) discloses phosphinic acidderivatives having activity as GABA_(B) antagonists.

General absence (petit mal) seizures are a clinically and experimentallyunique class of seizures, typically occuring in children. It has beenreported that GABA_(B) antagonists are effective in blocking theoccurrence of petit mal seizures in a number of animal models: SneadIII, Pharmacology Communications, 2 (1-2), pp. 63-69 (1992); Hosford, etal, Pharmacology Communications, 2 (1-2), pp. 123-124 (1992).

Mondadori, et al, Pharmacoloay Communications, 2 (1-2), pp. 93-97(1992), disclose the use of GABA_(B) receptor antagonists for improvingcognitive performance in animal models.

Bowery, et al, Arzneim. -Forsch./Drug Res., 42 (I), Nr. 2a, pp. 215-223(1992) relates to the physiological role of GABA_(B) receptorantagonists.

Morpholine and thiomorpholine derivatives bearing substituents at the 2position are known. Loftus, Syn. Comm., 10 (1), 59-73 (1980), disclosescompounds of the formula ##STR2## wherein R is methyl or benzyl.

European Patent Publication EP 398426 discloses compounds of the formula##STR3## wherein: X is O or S; P is C₆ H₅ --CH₂ -- or C₆ H₅ --CH₂--O--C(O)--; R¹⁷ is C₁ -C₄ alkoxy or OH; W is a reactive leaving group,such as halogen or sulfonyloxy; and Het represents a heteroaryl group.

European Patent Publication EP 311948 discloses compounds of the formula##STR4## wherein Z is a Cl, Br, I, --OSO₂ CH₃ or --OSO₂ --C₆ H₄ --CH₃.

SUMMARY OF THE INVENTION

Novel compounds of the present invention are represented by the formulaI ##STR5## wherein: X is O or S;

Y represents --CO₂ H, --CO₂ R⁶, --C(O)NHR⁷, --SO₃ H, --SO₂ H, --SO₃ R⁶,--SO₂ NHR⁷, --C(O)--N(OH)--R⁸, or a group of the formula ##STR6## R isselected from the group consisting of H, C₁ -C₈ alkyl, C₁ -C₈ alkanoyl,C₁ -C₈ alkoxycarbonyl, C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkyl(C₁-C₈)alkyl, Ar--(C₁ -C₈)alkyl and Ar--CH₂ --O--C(O)--;

Ar represents phenyl optionally substituted by 1 to 3 substituentsselected from C₁ -C₆ alkyl, halogeno, --CN, --NO₂, --CF₃, --OH, --OR⁶and --OCF₃ ;

R¹ and R² are independently substituents attached at the 2-, 3-, 5- or6- position of the heterocyclic ring;

R¹ is selected from the group consisting of C₁ -C₈ alkyl and hydroxy(C₁-C₈)alkyl; and

R¹ also represents H where:

(a) R is H and R⁷ is C₁ -C₆ alkyl or ##STR7## (b) X is S; or (c) Y is--SO₃ H, --SO₂ H, --SO₃ R⁶, --SO₂ NHR⁷, or a group of the formula##STR8## R² is selected from the group consisting of H, C₁ -C₈ alkyl andhydroxy(C₁ -C₈)alkyl; or

where R¹ and R² are attached at adjacent positions of the heterocyclicring: R¹ and R² together with the carbon atoms to which they areattached may also comprise a fused 3-8 membered carbocyclic ring, whichring may be optionally substituted by an --OH group; or

where R¹ and R² are attached at the same position of the heterocyclicring: R¹ and R² together with the carbon atom to which they are attachedmay also comprise a 3-8 membered carbocyclic spiro ring, which ring maybe optionally substituted by an --OH group;

R³ is H, C₁ -C₈ alkyl or hydroxy(C₁ -C₈)alkyl;

R⁶ is C₁ -C₆ alkyl;

R⁷ is H, C₁ -C₆ alkyl or ##STR9## R⁸ is H, C₁ -C₈ alkyl, C₃ -C₈cycloalkyl, C₃ -C₈ cycloalkyl(C₁ -C₈)alkyl, Ar or Ar--(C₁ -C₈)alkyl;

or a pharmaceutically acceptable addition salt or solvate thereof.

Preferred are compounds of the formula Ia, ##STR10## i.e., compounds ofthe formula I wherein R¹ and R² are both attached at the 5- position ofthe heterocyclic ring.

Also preferred are compounds of the formula I wherein Y is --CO₂ H,--CO₂ R⁶, --C(O)NHR⁷, or --C(O)--N(OH)--R⁸.

Another group of preferred compounds are compounds of the formula Iwherein Y is a group of the formula ##STR11##

Yet another group of preferred compounds are compounds of formula Iwherein R is hydrogen.

Still another group of preferred compounds are compounds of the formulaI wherein X is O.

Compounds wherein R³ is H are also preferred.

More preferred are compounds of the formula Ia wherein Y is --CO₂ H,--CO₂ R⁶, --C(O)NHR⁷, or --C(O)--N(OH)--R⁸.

Another group of more preferred compounds are compounds of the formulaIa wherein R is hydrogen.

Yet another group of more preferred compounds are compounds of formulaIa wherein R² is hydrogen and R¹ is --CH₃, --C₂ H₅ or --CH₂ OH.

Still another group of more preferred compounds are compounds of theformula Ia wherein Y is a group of the formula ##STR12##

Also more preferred are compounds of the formula Ia wherein R¹ and R²are independently selected from the group consisting of --CH₃, --C₂ H₅and --CH₂ OH.

Still another group of more preferred compounds are compounds of theformula Ia wherein R¹ and R², together with the carbon atom to whichthey are attached, comprise a 3-8 membered carbocyclic spiro ring, whichring is optionally substituted by an --OH group.

Most preferred are compounds of the formula Ia wherein R and R³ are bothhydrogen and Y is --CO₂ H or a group of the formula ##STR13##

Especially preferred are compounds having the structural formula##STR14##

This invention also comprises a pharmaceutical composition comprising aneffective amount of a compound of Formula I in combination with apharmaceutically acceptable carrier.

This invention further comprises a method for treating petit malseizures in a mammal comprising administering to the mammal an effectiveamount of a compound of Formula I.

Additionally, this invention comprises a method for treating cognitivedisorders in a mammal comprising administering to the mammal aneffective amount of a compound of Formula I.

This invention also comprises a method for treating respiratorydepression associated with GABA_(B) receptor stimulation comprisingadministering to a mammal in need of such treatment an effective amountof a compound of Formula I.

DETAILED DESCRIPTION

As used herein, the definitions of the following terms are applicable:

"alkyl" means straight or branched alkyl chains of 1 to 8 carbon atoms,and "alkoxy" similarly refers to alkoxy groups having 1 to 8 carbonatoms;

"alkanoyl" means "alkyl-C(O)--";

"alkoxycarbonyl" means "alkyl-O--C(O)--";

"cycloalkyl" means a saturated carbocyclic ring having from 3 to 8 ringmembers;

"halogeno" means a fluorine, chlorine, bromine or iodine radical;

"leaving group" means a group which can be readily displaced by anucleophile, such as Cl, Br, I or an alkylsulfonyl group of the formulalkyl-SO₃ --;

"counterion" means a cation, such as Na⁺, K⁺, Li⁺, Cs⁺, NH₄ ⁺, Ca⁺⁺ orMg⁺⁺.

Where reference is made to numbered positions of the heterocyclic ring,the numbered positions refer to numbering of the ring atoms as follows:##STR15##

Certain compounds of the invention are acidic, e.g., those compoundswhich possess a carboxylic, sulfonic, phosphinic or phosphonic acidgroup. These compounds form pharmaceutically acceptable salts withinorganic and organic bases. Examples of such salts are the sodium,potassium and calcium salts. Also included are salts formed withpharmaceutically acceptable amines such as ammonia, alkyl amines,hydroxyalkylamines, N-methylglucamine and the like.

The salts may be formed by conventional means, as by reacting the freeacid form of the product with one or more equivalents of the appropriatebase in a solvent or medium in which the salt is insoluble, or in asolvent such as water which is then removed in vacuo or by freeze-dryingor by exchanging the cations of an existing salt for another cation on asuitable ion exchange resin.

Certain compounds of the invention are basic, e.g. those compounds whichpossess a basic nitrogen atom. These compounds form pharmaceuticallyacceptable salts with organic and inorganic acids. Examples of suitableacids for such salt formation are hydrochloric, sulfuric, phosphoric,acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic,ascorbic, maleic, methanesulfonic and other mineral and carboxylic acidswell known to those skilled in the art. The salts are prepared bycontacting the free base form with a sufficient amount of the desiredacid to produce a salt in the conventional manner. The free base formsmay be regenerated by treating the salt with a suitable dilute aqueousbase solution such as dilute aqueous NaOH, K₂ CO₃, NH₃ and NaHCO₃. Thefree base forms differ from their respective salt forms somewhat incertain physical properties, such as solubility in polar solvents, butthe salts are otherwise equivalent to their respective free base formsfor purposes of this invention.

Certain acidic or basic compounds of the present invention may exist aszwitterions.

Certain compounds of the present invention can form solvates with anappropriate pharmacologically acceptable solvent such as water. Suchsolvates can also form with the salts or zwitterions of compounds of thepresent invention, as defined above.

Compounds of the formula I have at least one asymmetrical carbon atomand therefore include various stereoisomers. The invention includes allsuch isomers both in pure form and in admixture, including racemicmixtures.

The following solvents and reagents employed in preparing compounds ofthe present invention are identified by the terms or abbreviationsindicated: diethyl ether (Et₂ O); ethyl acetate (EtOAc); methanol(MeOH); ethanol (EtOH); dimethylformamide (DMF); tetrahydrofuran (THF);acetic acid (AcOH); N,N-diisopropylethylamine (Hunig's Base);triethylamine (NEt₃); 1,8-diazabicyclo 5.4.0!undec-7-ene (DBU);4-dimethylaminopyridine (DMAP); dimethylsulfoxide (DMSO);dicyclohexylcarbodiimide (DCC);1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (DEC); borontrifluoride etherate (BF₃.OEt₂); iso-propyl alcohol (IPA);triphenylphosphine (TPP); m-chloroperbenzoic acid (MCPBA).

Compounds of the present invention can be prepared via methods known tothose skilled in the art. For example, compounds of the formula Ib,i.e., compounds of the formula I wherein X is O and Y is --CO₂ R⁶, canbe prepared from an amino alcohol of the formula II or V with acrotonate ester of the formula III or VI, respectively, as shown inReaction Scheme A, wherein R, R¹, R² and R³ are as defined above, and Lis a leaving group, such as Cl, Br or I. The reaction is carried out ina suitable solvent, such as CH₂ Cl₂, in the presence of a tertiary aminebase, such as NEt₃ or Hunig's base, to form a compound of the formulaIV, from compounds II and III, or VII, from compounds V and VI.Compounds of the formula IV or VII are cyclized by heating in thepresence of a suitable base, such as DBU, in a high boiling solvent,such as toluene to give a compound of the formula Ib. ##STR16##

Compounds of the formula Ib, Ie or If can be converted to compounds ofthe formula Ic, i.e., compounds of the formula I wherein Y is --CO₂ H,by hydrolysis with a strong inorganic acid, preferably HCl, mostpreferably 1N to 6N aqueous HCl. ##STR17##

Compounds of the formula Ib, wherein R is H, or compounds of the formulaIe, can be converted to compounds of the formula If, i.e., compounds ofthe formula I, wherein Y is --CO₂ R⁶ and R is C₁ -C₈ alkyl, C₁ -C₈alkanoyl, C₁ -C₈ alkoxycarbonyl, C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkyl(C₁-C₈)alkyl, Ar--(C₁ -C₈)alkyl and Ar--CH₂ --O--C(O)--, and Ar is asdefined above, by alkylation or acylation with a compound of the formulaR--L, wherein R is C₁ -C₈ alkyl, C₁ -C₈ alkanoyl, C₁ -C₈ alkoxycarbonyl,C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkyl(C₁ -C₈)alkyl, Ar--(C₁ -C₈)alkyl andAr--CH₂ --O--C(O)--, Ar is as defined above, and L is a leaving group,such as Cl, Br or I. ##STR18##

Compounds of the formula Ic can be converted to compounds of the formulaId, i.e., compounds of the formula I wherein Y is --C(O)NHR⁷ or--C(O)--N(OH)--R⁸, by coupling with an amine of the formula R⁷ --NH₂,wherein R⁷ is as defined above, or a hydroxylamine of the formula R⁸--NH--OH, wherein R⁸ is as defined above, in the presence of a couplingagent, such as DCC or DEC, and a suitable base, such as DMAP. Forcompounds of the formula Ic wherein R is H, the nitrogen of themorpholine ring can be protected with a suitable amine protecting groupprior to the coupling reaction, followed by deprotection when thereaction is complete. Similarly, the hydroxy portion of thehydroxylamine can be protected using a suitable hydroxyl protectinggroup prior to the coupling reaction, followed by deprotection when thereaction is complete. ##STR19##

Compounds of the formula Ie, i.e., compounds of the formula I wherein Xis S, and Y is --CO₂ R⁶, wherein R⁶ is as defined above, are prepared byreacting a thiazolidine of the formula VIII or X and a crotonatederivative of the formula VI or III, respectively, as shown in ReactionScheme B, wherein R, R¹, R² and R³ are as defined above. The reaction iscarried out in a suitable solvent, such as THF, in the presence of atertiary amine base, such as NEt₃ or Hunig's base, to give a compound ofthe formula IX, from compounds of the formula VIII and VI, or a compoundof the formula XI, from compounds of the formula X and HI. Compounds ofthe formula IX or XI are cyclized by heating in an alcohol solvent, suchas methanol, in the presence of a strong inorganic acid, such as HCl,preferably 6N aqueous HCl, to give compounds of the formula Ie.##STR20##

In an alternative method for preparing compounds of the formula Ie, anaziridine of the formula XII or XIV is reacted with a compound of theformula VI or III, respectively, as shown in Reaction Scheme C, whereinR, R¹, R² and R³ are as defined above. The reaction is carried out in asuitable solvent, such as THF, in the presence of a tertiary amine base,such as NEt₃ or Hunig's base, to give a compound of the formula XIII,from compounds of the formula XII and VI, or a compound of the formulaXV, from compounds of the formula XIV and III. Compounds of the formulaXIII or XV are treated with thioacetic acid to form compounds of theformula XVI or XVII, respectively, which are hydrolyzed with a strongbase, such as NaOH, preferably 1N NaOH (aqueous), and acidified using astrong inorganic acid, such as HCl, preferably about 6N aqueous HCl, togive a compound of the formula Ie. ##STR21##

Compounds of the formula Ig, i.e., compounds of the formula I, wherein Xis O and Y is ##STR22## are prepared by reacting a compound of theformula II or V with a compound of the formula XVIII or XIX,respectively, as shown in Reaction Scheme D, wherein Q represents##STR23## and R, R¹, R², R³, R⁶ and R⁸ are as defined above. Thereaction is carried out by heating a mixture of II and XVIII, or V andXIX, in a suitable solvent, such as toluene, in the presence of a strongorganic base, such as DBU. For compounds of the formula Ig wherein R isH, the nitrogen of the morpholine ring can be protected with a suitableamine protecting group prior to the coupling reaction, followed bydeprotection when the reaction is complete. ##STR24##

Compounds of the formula XVIII and XIX are prepared from dibromides ofthe formula XX and XXI, respectively, wherein R² and R³ are as definedabove, by reacting with a compound of the formula P(R⁸)(OR⁶)₂ orP(OR⁶)₃, wherein R⁶ and R⁸ are as defined above. ##STR25##

Compounds of the formula Ig or Im can be converted to compounds of theformula Ih wherein Z is --OH or --R⁸ and R⁸ is as defined above, i.e.,compounds of the formula I wherein X is O or S, and Y is ##STR26## byhydrolysis using a base, such a NaOH. ##STR27##

Compounds of the formula Ig are also prepared by reacting a compound ofthe formula XXII, wherein L is a leaving group, preferably l, and R, R¹,R² and R³ are as defined above, with a compound of the formulaP(R⁸)(OR⁶)₂ or P(OR⁶)₃, wherein R⁶ and R⁸ are as defined above.##STR28##

Compounds of the formula Ih, i.e., compounds of the formula I, wherein Xis O, Y is --SO₃ H, L is a leaving group and R, R¹, R² and R³ are asdefined above, are prepared from compounds of the formula XXII by themethod shown in Reaction Scheme E. A compound of the formula XXII isreacted with a commercially available thiol of the formula Pr-SH,wherein Pr is a suitable sulfur protecting group, such as benzyl, toform a sulfide of the formula XXIII. The sulfide XXIII is deprotectedand the resulting thiol XXIV is oxidized to give a compound of theformula Ih. ##STR29##

Compounds of the formula Ii, i.e., compounds of the formula I, wherein Xis O and Y is ##STR30## are prepared from compounds of the formula XXIIas shown in Reaction Scheme F, wherein R, R¹, R² and R³ are as definedabove. A compound of the formula XXII is reacted with a cyanide salt,such as NaCN or KCN, to form a compound of the formula XXV. Compounds ofthe formula XXV are treated with sodium azide and ammonium chloride toform compounds of the formula Ii. ##STR31##

Compounds of the formula I wherein X is O and Y is --SO₃ R⁶ or --SO₂NHR⁷ are prepared from compounds of the formula Ih via known methods.

Compounds of the formula Ik, i.e., compounds of the formula I, wherein Xis S and Y is ##STR32## are prepared from compounds of the formula Ie orIf (wherein X is S) as shown in Reaction Scheme G, wherein R, R¹, R², R³and R⁶ are as defined above. A compound of the formula Ie or If isreacted with ammonia to form a primary amide of the formula XXVI. Theamide XXVI is dehydrated to form a nitrile of the formula XXVII, whichis converted to a compound of the formula Ik by treating with sodiumazide and ammonium chloride. Where a compound of the formula Ie is usedin Reaction Scheme G, the nitrogen of the thiomorpholine ring can beprotected with a suitable amine protecting group, such as benzyl orbenzyloxycarbonyl, prior to treatment with ammonia. Compounds of theformula Ik where R is H are then obtained by deprotection aftertetrazole formation. ##STR33##

Compounds of the formula Im, i.e., compounds of the formula I wherein Xis S and Y is ##STR34## are prepared by reacting an aziridine of theformula XII or XIV with a compound of the formula XXVIII or XXX,respectively, as shown in Reaction Scheme H, wherein R, R¹, R², R³, R⁶and R⁸ are as defined above. The reaction is carried out in the presenceof a tertiary amine base, such as NEt₃ or Hunig's base, to give acompound of the formula XXIX, from compounds of the formula XII andXXVIII, or a compound of the formula XXXI, from compounds of the formulaXIV and XXX. Compounds of the formula XXIX or XXXI are treated withthiolacetic acid, optionally in the presence of a Lewis acid, such asBF₃.OEt₂, to form a thiolacetate of the formula XXXII or XXXIII,respectively. Cyclization by treating XXXII or XXXIII in a suitablesolvent with dilute base, such as 1N to 2N NaOH (aqueous), gives rise toa compound of the formula XXXIV. Compound XXXIV is reacted with acompound of the formula R--L, as defined, to form a compound of theformula XXXV. The hydroxyl group of XXXV is converted to a leaving groupLG, selected from --Br, --I and --OSO₂ CF₃, by treating with HBr, HI ortrifluoromethanesulfonic anhydride, and the resulting compound XXXVItreated with a compound of the formula P(R⁸)(OR⁶)₂ or P(OR⁶)₃, whereinR⁶ and R⁸ are as defined above, to form a compound of the formula Im,wherein Q is as defined above. For compounds of the formula Im wherein Ris H, the nitrogen of the thiomorpholine ring of compound XXXIV can beprotected with a suitable amine protecting group, in which case thereaction with R--L is not performed. Deprotection after completion ofthe reaction scheme results in the formation of a compound of theformula Im wherein R is H. ##STR35##

Compounds of the formula In, i.e., compounds of the formula I wherein Xis O and Y is --SO₂ H or --SO₃ H, are prepared by reacting a chloride ofthe formula XLI, wherein R, R¹, R² and R³ are as defined above, with2-mercaptobenzotriazole (XLII), wherein ##STR36## as shown in ReactionScheme J. The reaction is carried out by heating in a suitable solvent,such as DMF, in the presence of a base, such as K₂ CO₃ or Cs₂ CO₃ togive the product XLIII. The product XLIII is oxidized with a suitableoxidizing agent, such as MCPBA, to form the sulfonyl derivative XLIV.The sulfonyl derivative XLIV is then reduced by treating with a suitablereducing agent, such as NaBH₄, to form a sulfinate of the formula XLV,wherein M⁺ is a suitable counterion, such as Na⁺ or NH₄ ⁺. The sulfinateXLV can be further oxidized to the analogous sulfonate XLVI by treatingwith a suitable oxidizing agent, such as MCPBA. The sulfinate XLV or thesulfonate XLVI is then treated with TPP to form a compound of theformula In. Compounds of the formula In where R is H can be prepared byhydrogenation of a compound of the formula In wherein R is benzyl, inthe presence of a suitable catalyst, such as 5% or 10% Pd/C. Compoundsof the formula In are generally isolated as the zwitterion, as shown inReaction Scheme J. ##STR37##

Starting compounds of the formula XXII are known, as disclosed in EP311948 and EP 398426, or can be prepared by reacting a compound of theformula II or V with an allyl bromide XXXVII or XXXVIII, respectively,as shown in Reaction Scheme K, to form a compound of the formula XXXIX,from compounds of the formula II and XXXVII, or XL, from compounds ofthe formula V and XXXVII. Compounds of the formula XXXIX and XL areconverted to compounds of the formula XXII by treating with iodine inthe presence of a suitable base. ##STR38##

Starting compounds of the formulae II, III, V, VI, VIII, XII, XIV, XX,XXI, XXVII, XXX, XXXVII, XXXVII, XLI and XLII are either commerciallyavailable or can be prepared from commercially available startingmaterials using known methods.

Reactive groups not involved in the above processes can be protectedduring the reactions with conventional protecting groups which can beremoved by standard procedures after the reaction. The following tableshows some typical protecting groups:

    ______________________________________    Group to be protected                 Protected Group    ______________________________________    --COOH       --COOalkyl, --COObenzyl, --COOphenyl    1 #STR39##                 2 #STR40##                 3 #STR41##                 4 #STR42##    5 #STR43##                 6 #STR44##    --OH         --OCH.sub.3    --NH.sub.2                 7 #STR45##    ______________________________________

The compounds of the invention possess GABA_(B) antagonistic properties.The compounds of the invention are, therefore, useful when stimulationof GABA_(B) receptors is a factor in the disease or disorder. Thisincludes treatment or prevention of: central nervous system disorders,including anxiety, depression, general absence or petit mal seizures andconditions requiring enhancement of cognitive performance; andrespiratory depression associated with GABA_(B) receptor stimulation,e.g. such as occurs during baclofen treatment.

The utility of the compounds of the present invention as GABA_(B)antagonists is demonstrated by using the following in vitro assayprocedures:

GABA_(B) Receptor Binding Assay

The percentage inhibition of GABA binding to GABA_(B) receptors ismeasured by tritiated GABA ( ³ H!GABA) determination of the degree ofbinding by scintillation counting. Rat brain synaptosomes are used as asource of GABA_(B) receptors. An incubation medium is prepared from thefollowing: 20 μg/mL of the compound to be tested as a solution in 1%DMSO/water; 5 nM ³ H!GABA; 50 mM Tris buffer (pH 7.5); and 2.5 mM CaCl₂.The medium also contains 40 μM isoguvacine to selectively block bindingto GABA_(A) receptors. The synaptosome (200 μg/mL) is added to theincubation medium and incubated for 30 minutes at 20° C. The incubationis terminated by filtration and counted to determine the percentageinhibition of ³ H!-GABA binding. The results are reported as IC₅₀ valuesfor those compounds inhibiting ³ H!-GABA binding by >50%.

In Vitro Assay

Male Hartley guinea pigs (450-650 g) are sacrificed by stunning and thetrachea removed proximal to the carina and cut into 5 mm segments. Thesegments are attached to isometric force displacement transducers (ModelFT03: Grass Instruments) and suspended in 15 mL organ baths filled withlow Ca²⁺ (0.6 mmol/L) Tyrode's buffer solution (pH 7.4) supplementedwith 5.6 mmol/L glucose, 30 μmol/L choline and 2 μmol/L indomethacin.The solution is bubbled with a mixture of 95% O₂ +5% CO₂ and maintainedat 37° C. The tracheal segments are allowed to equilibrate for 90minutes under a resting tension of 0.5 g.

Platinum electrodes are placed on either side of the trachea andelectrical field stimulation (EFS) (20 V, 8 Hz, 0.5 ms pulse for 5 s)was generated each minute from an electrical stimulator (Model S-88:Grass Instruments) and delivered to the electrodes through a stimulusdistributor (Buxco Electronics). The stimulation parameters are chosenas appropriate for producing cholinergic contractions of the tracheathat are sensitive to the inhibitory effects of compounds acting atprejunctional GABA_(B) receptors. Contractile responses were recorded ona polygraph (Harvard Apparatus). The compound to be tested is added tothe bath 10 min. before addition of 30 μmol/L baclofen. The effect ofbaclofen treatment in the absence or in the presence of the compound tobe tested is expressed as a percent inhibition of EFS-inducedcontractions. For compounds that caused greater than 30% inhibition ofthe response to 30 μmol/L baclofen, results are expressed as IC₃₀values.

The utility of the compounds of the present invention is furtherdemonstrated by using the following in vivo test procedures.

Animal Models for Absence Seizures

A. Snead, Eur. J. Pharmacol., 213, 343-349 (1992), teaches apharmacological model for testing the effectiveness of GABA_(B)antagonists in preventing seizures induced by intra-peritoneal (ip)administration of either γ-butyrolactone (GBL) or pentylenetetrazole(PTZ) to rats. The animal is treated with the test compound, thenmonitored after being subjected to a dose of either GBL or PTZsufficient to induce seizures. The in vivo activity of the compounds ofthe present invention can be demonstrated using the procedures describedtherein.

B. Hosford, et al., Science, 257, 398-401 (Jul. 17, 1992), teaches apharmacological model for testing the effectiveness of GABA_(B)antagonists as anticonvulsants for the treatment of absence seizures byadministering the compound to be tested to lethargic (lh/lh) mice, amutant strain with spontaneous seizures. The in vivo activity of thecompounds of the present invention can be demonstrated using theprocedures described therein.

Animal Model for Respiratory Depression:

Place unanesthetized guinea pigs in a head-out plethysmograph and exposeto a CO₂ enriched gas mixture (10% CO₂, 21% O₂, 69% N₂) for 10 min.,(see Danko, et al., J. Pharm. Methods, 19, 165-173 (1988)).Plethysmograph pressure is detected with a transducer connected to achart recorder. Minute ventilation is calculated as the product of tidalvolume and respiratory frequency. The compound to be tested isadministered orally, subcutaneously (sc), intraperitoneally (ip) or viaan intracerebroventricular route (icv). Baclofen (3 mg/kg, sc) was given30 min before exposure to the CO₂ enriched gas. When given by the oralroute, the compounds is administered 1, 3, 5 or 7 h before exposure toCO₂ enriched gas. A 40 or 30 min. preteratment is used for thesubcutaneous and intraperitoneal routes, respectively. The vehicle fororal, sc or ip administration is saline. For icv administration, singleicv cannulae are placed in the lateral ventricle of anesthetized guineapigs, (see McLeod, et al., Eur. J. Pharmacol., 209, 141-142 (1988)). Theanimals are allowed to recover approximately one week prior to use forventilation experiments. The vehicle for icv administration isartificial cerebrospinal fluid (CSF).

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 70 percentactive ingredient. Suitable solid carriers are known in the art, e.g.magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets,powders, cachets and capsules can be used as solid dosage forms suitablefor oral administration.

For preparing suppositories, a low melting wax such as a mixture offatty acid glycerides or cocoa butter is first melted, and the activeingredient is dispersed homogeneously therein as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool and thereby solidify.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection.

Liquid form preparations may also include solutions for intranasaladministration.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component, e.g., an effectiveamount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 10 mg to 3000 mg, more preferably fromabout 30 mg to 1000 mg, according to the particular application. Theappropriate dosage can be determined by comparing the activity of thecompound with the activity of a known GABA_(B) antagonist such as CGP35348.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage for a particular situation is withinthe skill of the art. Generally, treatment is initiated with smallerdosages which are less than the optimum dose of the compound.Thereafter, the dosage is increased by small increments until theoptimum effect under the circumstances is reached. For convenience, thetotal daily dosage may be divided and administered in portions duringthe day if desired.

The amount and frequency of administration of the compounds of theinvention and the pharmaceutically acceptable salts or solvates thereofwill be regulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddosage regimen is oral administration of from 10 mg to 3000 mg/daypreferably 30 to 1000 mg/day, in one to four divided doses to achieverelief of the symptoms. The compounds are non-toxic when administeredwithin this dosage range.

Following are illustrative examples of procedures for preparingcompounds of formula I.

PREPARATIVE EXAMPLE 1 ##STR46##

Add 5.2 mL of Hunig's Base to a solution of 1.8 g of2-amino-2-methyl-1-propanol and 3.3 mL of ethyl 4-bromocrotonate in 40mL of CH₂ Cl₂. Stir the solution at room temperature for 24 h, thenconcentrate under reduced pressure to a residue. Suspend the residue in60 mL of EtOAc and stir for 0.5 h, then filter. Concentrate the filtrateunder reduced pressure to yield a crude product. Purify the product byflash chromatography (silica gel, 95:5 CH₂ Cl₂ :MeOH/NH₃) to yield 2.5 gof the title compound, mp 71-73° C.

PREPARATIVE EXAMPLE 2 ##STR47##

Add 5 g of ethyl 4-bromocrotonate and 6 mL of NEt₃ to a solution of 2 gof 1-aminocyclopentanemethanol in 60 mL of EtOH. Heat the solution atreflux temperature for 18 h, then cool to room temperature andconcentrate in vacuo to a residue. Dissolve the residue in 150 mL ofwater and extract with 4×50 mL of CH₂ Cl₂. Wash the combined organicextracts with water and then with brine. Dry the organic extracts usingMgSO₄, filter and evaporate the filtrate under reduced pressure toproduce 1.85 g of crude product. Purify by flash chromatography (silicagel, CH₂ Cl₂ /10% MeOH) to yield 0.67 g of the title compound.

PREPARATIVE EXAMPLE 3 ##STR48##

Suspend 4 g of 1-aminocyclopropanemethanol hydrochloride in 60 mL ofEtOH. Add 10 mL of NEt₃ and stir the mixture at room temperature for 0.5h. Add 8 g of ethyl 4-bromocrotonate and stir for 18 h. Concentrate invacuo to a residue. Dissolve the residue in 150 mL of water and extractwith 4×50 mL of CH₂ Cl₂. Wash the combined organic extracts with brine,dry over MgSO₄, then filter and concentrate in vacuo to yield 4.5 g ofcrude product. Purify by flash chromatography (silica gel, EtOAc) toyield 2.1 g of the title compound. ¹ H-NMR shows the cyclopropyl protonsat ca. δ=0.55 and 0.75 ppm, and the vinyl protons at ca. δ=6.04 and 7.05ppm.

PREPARATIVE EXAMPLE 4 ##STR49##

Add 10 mL of NEt₃ to a mixture of 5 g of (R)--(--)-2-amino-1-butanol and13 g of ethyl 4-bromocrotonate in 120 mL of CH₂ Cl₂. Stir the solutionat room temperature for 4 h. Add CH₂ Cl₂ sufficient to bring the totalvolume to 250 mL and wash with 3×100 mL of brine. Concentrate the CH₂Cl₂ solution in vacuo to yield 6.2 g of crude product. Purify by flashchromatography (silica gel, 30:1 EtOAc:MeOH) to yield 2.2 g of the titlecompound. ¹ H-NMR (CDCl₃) δ values in ppm: 7.06 (d of t, 1H); 6.07 (d oft, 1H); 4.26 (q, 2H); 3.34-3.75 (m, 4H); 1.55 (m, 2H); 1.34 (t, 3H);0.97 (t, 3H).

PREPARATIVE EXAMPLE 5 ##STR50##

Combine 3.3 g of 2-benzylamino-1-propanol, 4 mL of ethyl4-bromocrotonate, and 25 mMol of DBU in 100 mL of toluene and heat themixture at reflux for 24 h. Concentrate in vacuo to a residue anddissolve the residue in CH₂ Cl₂ /H₂ O (100 mL/400 mL). Separate theaqueous layer and extract with 3×100 mL of CH₂ Cl₂. Combine the organiclayers and wash with brine. Dry the combine organic layers over MgSO₄,filter, then concentrate in vacuo to yield 4.2 g of crude product.Purify by flash chromatography (silica gel, 1:1 hexane/EtOAc) to produce2.4 g of the title compound.

PREPARATIVE EXAMPLE 6 ##STR51##

Prepare a solution of 1.6 mL of thiazolidine and 3 mL of NEt₃ in 30 mLof THF. Stir the solution, add 4.5 mL of ethyl 4-bromocrotonate, andstir the resulting mixture at room temperature for 60 h. Dilute thereaction mixture with 300 mL of EtOAc, wash with water and then withbrine, and dry over MgSO₄. Concentrate the organic solution in vacuo toyield 5.4 g of crude product. Purify by flash chromatography (silicagel, 2:1 hexane/EtOAc) to produce 4 g of the title compound. This wasused in the next step without further purification. (Example 18)

PREPARATIVE EXAMPLE 7 ##STR52## Step A:

Add 10 mL of NEt₃ to a solution of 9.2 mL of ethyl 4-bromocrotonate and4 mL of 2-methylaziridine in 100 mL of THF. Stir for 60 h, during whichtime a white precipitate forms. Dilute the reaction mixture with 300 mLof EtOAc and wash with water and then with brine. Dry the organicsolution over MgSO₄, filter, and concentrate in vacuo to yield 6.7 g ofcrude product. Purify by flash chromatography (silica gel, 1:4hexane/EtOAc) to yield 5.2 g of E-4-(2-methyl-1-aziridinyl)-2-butenoicacid ethyl ester.

Step B: ##STR53##

Treat 1.03 g of the product of step A with 0.5 mL of CH₃ COSH (asdescribed in J. Am. Chem. Soc., 77, 5144 (1955)) at 0° C. and stir themixture for 18 h. Confirm completion of the reaction by ¹ H-NMR. Purifythe mixture directly by flash chromatography (silica gel, EtOAc), toyield 1 g of the title compound.

PREPARATIVE EXAMPLE 8 ##STR54##

Dissolve 5 g of 2-amino-2-ethyl-1,3-propanediol and 9 g of ethyl4-bromocrotonate in 60 mL of THF. Add 15 mL of NEt₃ and stir at roomtemperature for 70 h. Dilute the reaction mixture with 300 mL of water,extract with 3×150 mL of CH₂ Cl₂, wash with brine, and dry over MgSO₄.Concentrate the combined extracts in vacuo to yield 5.5 g of crudeproduct. Purify by flash chromatography (silica gel, 95:5 EtOAc/MeOH) toyield 2.2 g of the title compound.

Using substantially the same procedure 2-amino-2-methyl-1,3-propanediolis converted to the following compound (Preparative Example 8A):##STR55##

mass spectrum (FAB) m/e 218 (M+1)⁺ =100% Elemental Analysis: calcd. forC₁₀ H₁₉ NO₄ ; C, 55.28; H, 8.81; N, 6.45. Found; C, 54.83; H, 8.58; N,6.40

PREPARATIVE EXAMPLE 9 ##STR56##

Cool 1.3 mL of diethyl methylphosphonite to 0° C., then slowly add(dropwise) 1 mL of a mixture of E- and Z-1,3-dibromo-propene. Stir themixture at 0° C. for 30 min., then allow the mixture to warm to roomtemperature and stir for 3 h. Add 0.7 mL of diethyl methylphosphoniteand stir for 18 h. at room temperature. Concentrate under vacuum to givethe title compound as a residue.

PREPARATIVE EXAMPLE 10 ##STR57##

Mass Spec. (FAB): (M+1)⁺ m/z=357

Step a:

Combine 1.13 g (5 mmol) of 4-benzyl-2-chloromethylmorpholine and 10 mLof DMF, add 0.84 g of 2-mercaptobenzothiazole and 3 g of Cs₂ CO₃ andstir at room temperature for a short time. Heat the mixture to 100°-105°C. and monitor the reaction by TLC (silica gel, 80:20 hexane/EtOAc).Cool the mixture to room temperature when the reaction is complete andadd 100 mL of Et₂ O, filter and wash the solid residue with Et₂ O. Washthe filtrate twice with H₂ O and concentrate to a residue. Purify theresidue by column chromatography (silica gel, 85:15 hexane/EtOAc), togive the product ##STR58## Step b:

Combine 1 g of the product of step a and 40 mL of CH₂ Cl₂, stir whilecooling to -20° to -15° C., and add 1.27 g of MCPBA. Monitor thereaction by TLC (silica gel, 91.5:7.5:1 CH₂ Cl₂ /MeOH/NH₃ (aqueous)).Add another 0.13 g of MCPBA and stir at 0° C. until the reaction iscomplete by TLC.

Wash the reaction mixture successively with 50 mL of 2% NaHSO₃(aqueous), 100 mL of saturated NaHCO₃ (aqueous), and brine, then dryover Na₂ SO₄. Concentrate resulting organic solution in vacuo to aresidue and purify by column chromatography (silica gel, 2%-10% MeOH inCH₂ Cl₂ +a few drops of NH₃ (aqueous)), to give the oxidized product offormula ##STR59##

Mass Spec. (FAB): (M+1)⁺ m/z=405

Step c:

Combine 1 g of the product of step b and 30 mL of EtOH. Stir the mixtureat room temperature and add 0.195 g of NaBH₄. Stir for 2 days, thenconcentrate in vacuo to a residue and purify by column chromatography(silica gel, 67% CH₂ Cl₂ :30% MeOH:3%NH₃ (aqueous), then 56% CH₂ Cl₂:40% MeOH:4%NH3(aqueous)) to give the product. Dissolve the product indeionized H₂ O and pass through a strongly acidic ion exchange column inthe NH₄ ⁺ form. Concentrate the resulting solution in vacuo to give thetitle compound, m.p. =95°-99° C. Mass Spec. (FAB): (M+1)⁺ m/z=272.

EXAMPLE 1 ##STR60##

Dissolve 1.78 g of the product of Preparative Example 1 and 0.18 g ofDBU in 50 mL of toluene and heat the solution at reflux for 18 h. Coolthe reaction mixture and remove the solvent under reduced pressure.Purify the resulting residue by flash chromatography (silica gel, 95:5CH₂ Cl₂ : MeOH/NH₃) to yield 1.2 g of the title compound.

Using substantially the same procedure the following compounds can alsobe prepared:

from the product of Preparative Example 3 ##STR61## from the product ofPreparative Example 2 ##STR62##

EXAMPLE 2 ##STR63##

Dissolve 0.6 g of the product of Example 1 in 10 mL of 6N HCl (aqueous).Heat the solution at reflux for 18 h, then concentrate in vacuo to yield0.5 g of the title compound, m.p. 204-206° C. Elemental Analysis, calcd.for C₈ H₁₅ NO₃.HCl; C, 45.82; H, 7.69; N, 6.68. Found, C, 45.73; H,7.62; N, 6.41.

EXAMPLE 3 ##STR64##

Dissolve 6.6 g of the product of Example 1, 0.2 g of DMAP, and 10 mL ofbenzyl chloroformate in 200 mL of CH₂ Cl₂. Stir the solution and slowlyadd 10 mL of NEt₃ over a period of about 10 min. Stir the reactionmixture at room temperature for 6 h, then dilute with 300 mL of CH₂ Cl₂.Wash with 2×100 mL of water, and 150 mL of brine. Dry the organic layer(MgSO₄), then concentrate in vacuo to yield 14.5 g of crude product.Purify by flash chromatography (silica gel, 80:20 hexane:EtOAc) to yield9.1 9 of the title compound, m.p. =45.5°-46.5° C. Elemental Analysis:calcd. for C₁₈ H₂₅ NO₅ : C, 64.45; H, 7.51; N, 4.17; found: C, 64.51; H,7.44; N, 4.29.

EXAMPLE 4 ##STR65##

Dissolve 1 g of the product of Example 1 in ca. 10 mL of CH₂ Cl₂ at roomtemperature. Add a solution of 1.2 g of di-t-butyl-dicarbonate, in ca. 3mL of CH₂ Cl₂. After about 0.5 h add a few drops of Hunig's Base andallow the reaction mixture to stand at room temperature overnight.Concentrate in vacuo to a residue, dissolve the residue in EtOAc andwash with brine Concentrate the organic layer to yield the titlecompound, m.p. 360-380C. Elemental Analysis for C₁₅ H₂₇ NO₅. Calcd. C,59.78; H, 9.03; N, 4.65. Found, C, 60.00; H, 9.01; N, 5.37.

EXAMPLE 5 ##STR66##

The racemic product of Example 3 is separated into its individualenantiomers by the following procedure. Inject 2 to 4 mL of a 10%solution of the product of Example 3 in 95:5 hexane:isopropanol onto a50×500 mm Daicel Chiralcel OD® preparative HPLC column and elute with95:5 hexane:isopropanol. Smaller injections give complete separation ofthe enantiomers, whereas larger injections give some mixed fractionsbetween the two enantiomer peaks. The α-value for the separation isabout 1.38 when measured using the identical solvent on a DaicelChiralcel OD® analytical HPLC column. Combine pure fractions andevaporate the solvent to yield the two enantiomers, as follows:Enantiomer 1, Example 5A (eluting first from the column); Enantiomer 2,Example 5B (eluting second from the column):

EXAMPLE 6 ##STR67## Step A: ##STR68##

Dissolve 0.35 g of the product of Example 5A in 15 mL of a mixture of 1NNaOH (aqueous), MeOH, and THF (20:5:5), and stir the mixture at roomtemperature for 18 h. Add sufficient 1N HCl (aqueous) to bring the pHbelow 3, then dilute with EtOAc. Separate the organic layer, wash with10 mL of water and then with 20 mL of brine. Dry the organic solutionover MgSO₄, filter, and evaporate to yield 0.35 g of crude product.

Step B: ##STR69##

Dissolve the crude product of step A in 30 mL of methanol, add 100 mg of10% Pd on C, and agitate the mixture under an atmosphere of H₂ for 18 h.Add 4 mL of 1N HCl (aqueous), filter and concentrate the filtrate invacuo to yield 0.25 g of crude product. Purify by trituration with 1:9acetone/EtOAc to give 0.08 g of the (+)-enantiomer of the title compound(Example 6A), mp 142-144° C. Analysis, calcd. for C₈ H₁₅ NO₃.HCl: C,45.83; H, 7.69; N, 6.68; Found: C, 45.92; H, 7.58; N, 6.48. α!_(D)=+17.30° (21.50° C., H₂ O).

Using substantially the same two step procedure the product of Example5B is converted to the (-)-enantiomer of the title compound: ##STR70##

EXAMPLE 7 ##STR71##

The racemic product of Example 4 can be separated into its individualenantiomers by the following procedure. Prepare a 10% solution of theproduct of Example 4 in 95:5 hexane: isopropanol. Inject 2.5 to 5.0 mLof this solution (containing from 250 to 500 mg of compound) onto a50×500 mm Daicel Chiralcel OD® preparative HPLC column and elute with99:1 hexane:isopropanol. The two enantiomers are completely separatedunder these conditions in just under one hour at a flow rate of 50mL/min. The α-value for this separation is about 1.54. Combine the purefractions and evaporate the solvent to yield the two enantiomers of thetitle compound as follows:

Example 7A, (+)-enantiomer (eluting first): m.p.=56°-58° C. ElementalAnalysis: Calcd. for C₁₅ H₂₇ NO₅ ; C, 59.78; H, 9.03; N, 4.65. Found; C,59.91; H, 8.78; N, 4.65. α!_(D) +21.8° (23° C., MeOH)

Example 7B, (-)-enantiomer (eluting second): m.p. 56-58° C.; α!_(D)-20.6° (23° C., MeOH); Elemental Analysis: Calcd. for C₁₅ H₂₇ NO₅ ; C,59.78; H, 9.03; N, 4.65. Found; C, 59.79; H, 8.73; N, 4.64.

EXAMPLE 8 ##STR72##

An alternative method of preparing the products of Example 6A and 6B isas follows. The product of Example 7B is hydrolyzed according to theprocedure described in Example 6, Step A, to give the (-)-enantiomer,Example 6B, m.p.=154.5°-157° C. Elemental Analysis: Calcd. for C₈ H₁₅NO₃.HCl; C, 45.83; H, 7.69; N, 6.68. Found; C, 45.76; H, 7.46; N, 6.61.α!_(D) -18.7° (23° C., H₂ O)

In an analogous manner, the product of Example 7A is hydrolyzed to givethe (+)-enantiomer, Example 6A, m.p. =154.5°-157° C. Elemental Analysis:Calcd. for C₈ H₁₅ NO₃.HCl; C, 45.83; H, 7.69; N, 6.68. Found; C, 45.71;H, 7.62; N, 6.61. α!_(D) +16.5° (25° C., H₂ O)

EXAMPLE 9 ##STR73##

Heat a solution of 0.67 g of the product of Example 1 B in 25 mL of 1NHCl (aqueous) to reflux for 24 h. Cool to room temperature and treatwith activated charcoal at 80° C. for 30 min. Filter and concentrate thefiltrate in vacuo to give 0.75 g of crude product. Triturate withacetone to produce 0.56 g of the title compound, m.p. 186-188° C.Elemental Analysis, calcd. for C₁₀ H₁₇ NO₃.HCl.0.3H₂ O, C, 49.81; H,7.77; N, 5.80; Cl, 14.70. Found, C, 49.51; H, 7.47; N, 5.79; Cl, 14.86.

Using substantially the same procedure the product of Example 1A isconverted to the following compound, Example 9A: ##STR74##

mp 188-190° C. Elemental Analysis, calod. for C₈ H₁₄ NO₃ Cl.HCl.0.1H₂ O;C, 45.87; H, 6.83; N, 6.69; Cl, 16.93. Found; C,45.68, 45.74; H, 6.71,6.65; N, 6.78, 6.69; Cl, 16.99.

EXAMPLE 10 ##STR75##

Dissolve 2.2 g of the product of Preparative Example 4 and 200 mg of DBUin 150 mL of toluene, and heat the solution at reflux temperature for 6h. Concentrate in vacuo to a residue. Purify the residue by flashchromatography (silica gel, 97:3 CH₂ Cl₂ :MeOH/NH₃) to give the twodiastereomers of the title compound: ##STR76##

EXAMPLE 11 ##STR77##

Heat a mixture of 1.2 g of the product of Example 10 A and 30 ML of 1NHCl (aqueous) at reflux for 18 h. Concentrate in vacuo and triturate theresulting residue with acetone to give the title compound. Purify bydissolving in 20 mL of 1N HCl, washing this solution with 3×10 mL of CH₂Cl₂, then treating the aqueous layer with activated charcoal. Filter,then concentrate the filtrate in vacuo to yield 0.45 g of partiallypurified title compound. A further purification by dissolution in 1NHCl, charcoal treatment, and evaporation, as before, gives 0.25 g of thepurified title compound, m.p. 140-144° C.

EXAMPLE 12 ##STR78##

Heat a solution of 2.4 g of the product of Preparative Example 5 and 100mg of DBU in 100 mL of toluene at reflux for 18 h. Concentrate in vacuoto a residue which is purified by flash chromatography (silica gel,60:40 hexane/EtOAc) to yield 0.93 g of the cis-isomer (Example 13A) and0.9 g of the trans-isomer (Example 13B) of the title compound. (Theisomers are identified by ¹ H-NMR using a combination of couplingconstants and NOE observations.) ##STR79##

Using substantially the same procedure the product of PreparativeExample 8 is converted to: ##STR80## and the product of PreparativeExample 8A is converted to: ##STR81##

EXAMPLE 13 ##STR82##

Heat a mixture of ca. 0.9 g of the product of Example 12A and 30 mL of6N HCl (aqueous) at reflux for 18 h. Remove the solvent to yield 0.87 gof the crude product. Triturate with MeOH to give 0.7 g of the racemictitle compound, mp 211-213° C.

Using substantially the same procedure: the product of Example 12B isconverted to the trans-isomer of the title compound: ##STR83## theproduct of Example 17B is converted to: ##STR84##

mp 134-137° C. Analysis, calcd. for C₇ H₁₃ NO₂ S.HCl; C, 39.71; H, 6.67;N, 6.62. Found, C, 39.88, 39.82; H, 6.76, 6.62; N, 6.49, 6.59;

the product of Example 17A is converted to: ##STR85##

EXAMPLE 14 ##STR86##

Add 100 mg of 10% Pd on C to 0.7 g of the product of Example 13 and 20mL of 6N HCl. Hydrogenate the mixture under an atmosphere of H₂ at 60psi for 18 h. Filter and concentrate the filtrate in vacuo to yield 0.45g of the racemic title compound, m.p. 165-168° C.

Using substantially the same procedure the product of Example 13A isconverted to the trans-isomer of the title compound: ##STR87##

m.p. 219-221° C. Elemental Analysis: calcd. for C₇ H₁₃ NO₃.HCl: C,42.97; H, 7.21; N, 7.16; Cl, 18.12. Found, C, 42.79; H, 7.36; N, 6.95;Cl, 18.19.

EXAMPLE 15 ##STR88##

Heat a mixture of 4 g of the product of Preparative Example 6, 30 mL of6N HCl and 2 mL of MeOH at reflux for 24 h. Concentrate in vacuo to aresidue. Dissolve the residue in 100 mL of MeOH and treat with activatedcharcoal. Filter and concentrate the filtrate in vacua to give 3.5 g ofthe crude product. Suspend the product in 100 mL of EtOAc and let standat 0° to 10° C. for 2 weeks. Filter, wash the solid with EtOAc,isopropanol, and then MeOH, and dry to yield 0.85 g of the titlecompound, mp 139-141° C., mass spectrum (Cl) m/e 176 (M+1).

EXAMPLE 16 ##STR89##

Stir a mixture of 60 mg of the product of Example 15 and 4 mL of 1N NaOH(aqueous) at room temperature for 18 h. Concentrate in vacuo and treatthe residue with 4 mL of HCl in MeOH (concentrated). Filter andconcentrate the filtrate in vacuo to a residue. Treat the residue with 2mL of MeOH and 10 mL of CH₂ Cl₂, filter, then concentrate the filtratein vacuo to yield 50 mg of the title compound, mp 192-194° C. ElementalAnalysis; Calcd. for C₆ H₁₁ NO₂ S.HCl; C, 36.45; H, 6.12; N, 7.09.Found, C, 36.17; H, 5.89; N, 6.81.

EXAMPLE 17 ##STR90##

Combine 1 g of the product of Preparative Example 7 with 5 mL of 1NNaOH, 5 mL of water and 5 mL of MeOH, and stir at room temperature for18 h. Quench the reaction mixture with 4 mL of 6N HCl and concentrate invacuo to a residue. Treat the residue with MeOH, filter, and concentratethe filtrate in vacuo to yield 1.03 g of crude product. Treat the crudeproduct with HCl/MeOH for 60 h, then evaporate the solvent to give thetitle compound.

The title compound (4 g) can be separated into its cis and trans isomersby preparative HPLC (C₁₈ reversed phase column, 20:80 CH₃ CN/water) togive: ##STR91##

EXAMPLE 18 ##STR92##

Dissolve 0.8 g of the product of Example 12C in 20 mL of 1N HCl and heatto reflux for 18 h. Concentrate in vacuo to yield 0.7 g of crudeproduct. Triturate with acetone to produce 0.65 g of the title compound,mp 146-149° C. Analysis: C, 44.37; H, 7.58; N, 5.67. Calcd. for C₉ H₁₇NO₄.HCl.0.25H₂ O: C, 44.27; H, 7.64; N, 5.74.

EXAMPLE 19 ##STR93##

Dissolve 0.7 g of the product of Example 12D in 20 mL of 1 N HCl andheat at reflux for 18 h. Cool the reaction mixture and concentrate invacuo to yield 0.69 g of crude product. Dissolve in EtOH and treat withan excess of propylene oxide at 0° C. for 18 h. Concentrate in vacuo toa residue and triturate the residue with 3×5 mL of ether. Dissolve theresidue in 15 mL of water, add activated charcoal, heat for 5 min,filter, and concentrate in vacuo to yield 0.18 g of the title compound.

EXAMPLE 20 ##STR94##

Dissolve 3.3 g of the product of Example 12E in 100 mL of 1N HCl(aqueous) and stir for 3 days at room temperature. Concentrate to aresidue then triturate the residue with EtOAc to give 2.92 g of thetitle compound. Elemental analysis: calod.. for C₈ H₁₅ NO₄.HCl.2/3H₂ O,C, 40.43; H, 7.35; N, 5.89, found, C, 40.30; H, 7.29; N, 5.81.

EXAMPLE 21 ##STR95##

Dissolve 1.7 g of the product of Example 12F in 50 mL of 1N HCl and stirat room temperature for 3 days. Concentrate to a residue andchromatograph the residue (silica gel, 80:19:1 CH₃ CN/H₂ O/1N HCl).Triturate the purified product with IPA to yield 0.74 g of the titlecompound. MS (Cl) m/e 190 (M+1)⁺. Elemental analysis: calcd.. for C₈ H₁₅NO₄.HCl.1/2H₂ O, C, 40.94; H, 7.30; N, 5.97, found, C, 40.59; H, 6.70;N, 5.89.

EXAMPLE 22 ##STR96##

Combine 2.35 g of the product of Preparative Example 9, 3.3 g ofN-benzyl-2-aminoethanol and 30 mL of toluene and heat the mixture atreflux for 18 h. Dilute the mixture with 100 mL of water and 50 mL ofsaturated NaHCO₃ (aqueous). Extract with 4×70 mL of EtOAc, combine theorganic extracts and wash with brine. Dry the organic extracts overMgSO₄, filter and concentrate in vacuo to give 3.2 g of the crudeproduct. Purify by flash chromatography (silica gel, 7% MeOH in CH₂ Cl₂)to give 1.6 g of the title compound

EXAMPLE 23 ##STR97##

Combine 1.2 g of the product of Example 22 and 20 mL of concentrated HCland heat the mixture at reflux for 18 h. Cool the mixture andconcentrate in vacuo to give 1.08 g of crude product. Triturate with hotacetone to give 0.88 g of the title compound, m.p. 190°-192° C. FAB MS:m/e 270 (M+1)⁺.

EXAMPLE 24 ##STR98##

Combine 0.3 g of the product of Example 23, 20 mL of 1N HCl (aqueous)and 50 mg of 10% Pd/C and hydrogenate in a Parr shaker for 18 h. Filterand concentrate the filtrate in vacuo to give 0.21 g of crude product.Triturate with EtOAc and dry the solid under vacuum to give 0.2 g of thetitle compound. Elemental Analysis: calcd. for C₆ H₁₄ NO₃ P.HCl.H₂ O: C,30.85; H, 7.33; N, 6.00; found: C, 30.90; H, 6.63; N, 5.76; C, 30.88; H,6.64; N, 5.77.

EXAMPLE 25 ##STR99##

Combine 0.2 g of the product of Preparative Example 10 and 5 mL ofglacial HOAc. Add 1.1 equivalents of TPP and warm to 75° C. When thestarting compound is gone by TLC, cool to room temperature, concentratein vacuo to a residue and purify by column chromatography (silica gel,CH₂ Cl₂ /30%-40% MeOH/3%-4% NH₃ (aq.)), to give the title compound.

EXAMPLE 26 ##STR100## Step a:

Combine 0.25 g of the product of Preparation 10, 5 mL of CH₂ Cl₂ andenough MeOH to form a solution. Add MCPBA and stir at room temperature.Concentrate in vacuo to a residue, then purify by column chromatography(silica gel, CH₂ Cl₂ /MeOH/NH₃ (aq.)), to give the sulfonate product.

Step b:

The product of step a is converted to the title compound viasubstantially the same procedure as described for Example 25.

EXAMPLE 27 ##STR101##

Combine 0.5 g of the title compound of Example 26, 10 mL of MeOH and 50mg of 10% Pd/C. Agitate the mixture under H₂ atmosphere, then filter andconcentrate the filtrate in vacua to a residue. Purify the residue bycolumn chromatography to give the title compound.

Following substantially the same procedure, the title compound ofExample 25 is converted to a compound of the formula ##STR102##

Using the in vitro assay methods described above, the following datawere obtained:

    __________________________________________________________________________                            Binding In Vitro                            IC.sub.50 or                                    IC.sub.30 or    Example                 % inhibition                                    % inhibition    No.  Structure          (dose)  (dose)    __________________________________________________________________________         8 #STR103##        6 μM 96% (100 μM)                                    1.5 μM 100% (300 μM)         (recemic)    6A         9 #STR104##        2 μM 94% (100 μM)                                    1.1 μM 90% (30 μM)         (+)-enantiomer    6B         0 #STR105##        >100 μM 8% (100 μM)                                    42% (300 μM)         (-)-enantiomer    9         1 #STR106##        10 μM 95% (100 μM)                                    97% (300 μM)    9A         2 #STR107##        37 ± 12 μM 76% (100 μM)    11         3 #STR108##        14 μM 82% (100 μM)                                    95% (300 μM)    13B         4 #STR109##        60 μM 55% (100 μM)         (racemic)    13C         5 #STR110##        20 μM 81% (100 μM)                                    88% (300 μM)         (racemic)    14         6 #STR111##        20 μM 74% (100 μM)                                    95% (300 μM)         (racemic)    14A         7 #STR112##        30 μM 63% (100 μM)                                    75% (300 μM)         (racemic)    16         8 #STR113##        >100 44% (100 μM)                                    --    18         9 #STR114##        100 ± 40 μM 50% (100 μM)         (racemic)    19         0 #STR115##        19 ± 10 μM 90% (100 μM)                                    99% (300 μM)         (racemic)    --         1 #STR116##        50 μM 59% (100 μM)                                    46% (300 μM)    --         2 #STR117##        >100 μM 21% (100 μM)                                    --    --         3 #STR118##        100 μM 50% (100 μM)    --         4 #STR119##        >100 μM 17% (100 μM)    23         5 #STR120##        >100 μM 31% (100 μM)    24         6 #STR121##        6 μM 100% (100 μM)                                    98% (300 μM)    --         7 #STR122##        2 μM 100% (100 μM)                                    1.9 μM    20         8 #STR123##        3.8 μM                                    24% (30 μM)         (racemic)    21         9 #STR124##                0.85 μM         (racemic)    --         0 #STR125##        3 μM 3.3 μM    __________________________________________________________________________

Using the in vivo test methods described above, the following results(Tables A, B, C, D & E) were obtained using the compound of Example 6Aas the test compound:

                  TABLE A    ______________________________________    Prevention of seizure in rats induced by GBL             SWD.sup.1 duration (sec) at specified time    Test     (min) after treatment with    Compound 100 mg/kg GBL (ip)    Dose     20     40       60   80     100  120    ______________________________________    control  990    1150     500  300    75   5    0.75 mg/kg             970    1150     500  280    50   0    1.5 mg/kg             560    540      0    0      0    0    3.0 mg/kg             0      0        0    0      0    0    ______________________________________     .sup.1 Values are given as spiked wave discharge (SWD) duration in     seconds.

                  TABLE B    ______________________________________    Prevention of seizure in rats induced by PTZ             SWD.sup.1 duration (sec) at specified time    Test     (min) after treatment with    Compound 20 mg/kg GBL (ip)    Dose     20     40       60   80     100  120    ______________________________________    control  285    260      150  70     20   5    0.18 mg/kg             250    235      140  60     15   0    0.375 mg/kg             150    140      55   25     0    0    0.75 mg/kg             90     70       45   0      0    0    1.5 mg/kg             0      0        0    0      0    0    ______________________________________     .sup.1 Values are given as spiked wave discharge (SWD) duration in     seconds.

                  TABLE C    ______________________________________    Prevention of seizure in    lethargic (lh/lh) mice    Dose of Test  Seizures (% vehicle) in    Compound (ip) 120 min.    ______________________________________    vehicle alone 100%    1.0 mg/kg     85%    3.0 mg/kg     60%    10 mg/kg      15%    30 mg/kg       5%    ______________________________________

                  TABLE D    ______________________________________    Inhibition of Respiratory Depressant    Effect of Baclofen.sup.a    Dose     % Inhibition.sup.2                         % Inhibition.sup.2                                    % inhibition.sup.2    (mg/kg)  (sc)        (oral).sup.1                                    (ip)    ______________________________________    0.3      27 ± 6(6)                         --         39 ± 10(9)    1.0      66 ± 7(9)                         36 ± 13(6)                                    32 ± 7(15)    3.0      97 ± 25(6)                         51 ± 13(12)                                    59 ± 7(18)    10        99 ± 11(12)                         68 ± 13(12)                                    100 ± 9(18)    30       --          78 ± 29(11)                                    --    ED.sub.50 (mg/kg)             0.63        3.0        1.9    ______________________________________     .sup.a Baclofen alone inhibited ventilation 44-60%.     .sup.1 Test compound was given orally 60 min prior to baclofen.     .sup.2 Results are given as the mean ± SEM. Number in parentheses is     the number of animals tested.

                  TABLE E    ______________________________________    Reversal of the Respiratory Depressant    Effect of Baclofen via icv Administration.sup.a                    No. of Animals    Treatment.sup.1 tested     % Inhibition.sup.2    ______________________________________    50 μg in 10 μl of vehicle                    5          99 ± 23    ______________________________________     .sup.a Baclofen plus vehicle inhibited ventilation 82 ± 5%.     .sup.1 Given 5 min before measurement of ventilation.     .sup.2 Mean ± SEM

The following are examples of pharmaceutical dosage forms which containa compound of the invention. As used therein, the term "active compound"is used to designate a compound of the formula ##STR126##

The scope of the invention in its pharmaceutical composition aspect isnot to be limited by the examples provided, since any other compound offormula I can be substituted into the pharmaceutical compositionexamples.

Pharmaceutical Dosage Form Examples EXAMPLE A

    ______________________________________    Tablets    No.     Ingredients      mg/tablet                                      mg/tablet    ______________________________________    1.      Active compound  100      500    2.      Lactose USP      122      113    3.      Corn Starch, Food Grade,                             30       40            as a 10% paste in            Purified Water    4.      Corn Starch, Food Grade                             45       40    5.      Magnesium Stearate                             3        7            Total            300      700    ______________________________________

Method of Manufacture

Mix Item Nos. 1 and 2 in a suitable mixer for 10-15 minutes. Granulatethe mixture with Item No. 3. Mill the damp granules through a coarsescreen (e.g., 1/4", 0.63 cm) if necessary. Dry the damp granules. Screenthe dried granules if necessary and mix with Item No. 4 and mix for10-15 minutes. Add Item No. 5 and mix for 1-3 minutes. Compress themixture to appropriate size and weigh on a suitable tablet machine.

EXAMPLE B

    ______________________________________    Capsules    No.     Ingredient       mg/capsule                                       mg/capsule    ______________________________________    1.      Active compound  100       500    2.      Lactose USP      106       123    3.      Corn Starch, Food Grade                             40        70    4.      Magnesium Stearate NF                             7         7            Total            253       700    ______________________________________

Method of Manufacture

Mix Item Nos. 1, 2 and 3 in a suitable blender for 10-15 minutes. AddItem No. 4 and mix for 1-3 minutes. Fill the mixture into suitabletwo-piece hard gelatin capsules on a suitable encapsulating machine.

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand variations thereof will be apparent to those of ordinary skill inthe art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present invention.

We claim:
 1. A compound of the formula I ##STR127## wherein: X is O orS;Y represents --CO₂ H, --CO₂ R⁶, C--(O)NHR⁷, --SO₃ H, --SO₂ H, --SO₃R⁶, --SO₂ NHR⁷, --C(O)--N(OH)--R⁸, or a group of the formula ##STR128##R is selected from the group consisting of H, C₁ -C₈ alkyl, C₁ -C₈alkanoyl, C₁ -C₈ alkoxycarbonyl, C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkyl(C₁-C₈)alkyl, Ar--(C₁ -C₈)alkyl and Ar--CH₂ --O--C(O)--; Ar representsphenyl optionally substituted by 1 to 3 substituents selected from C₁-C₆ alkyl, halogeno, --CN, --NO₂, --CF₃, --OH, --OR⁶ and --OCF₃ ; R¹ isselected from the group consisting of C₁ -C₈ alkyl and hydroxy(C₁-C₈)alkyl; and R¹ also represents H where:(a) R is H and R⁷ is C₁ -C₆alkyl or ##STR129## (b) X is S; or (c) Y is --SO₃ H, --SO₂ H, --SO₃ R⁶,--SO₂ NHR⁷, or a group of the formula ##STR130## R² is selected from thegroup consisting of H, C₁ -C₈ alkyl and hydroxy(C₁ -C₈)alkyl; or whereR¹ and R² are both attached at the 5-position of the heterocyclic ring:R¹ and R² together with the carbon atom to which they are attached mayalso form a 3-8 membered carbocyclic spiro ring, which ring may beoptionally substituted by an --OH group; R³ is H, C₁ -C₈ alkyl orhydroxy(C₁ -C₈)alkyl; R⁶ is C₁ -C₆ alkyl; R⁷ is H, C₁ -C₆ alkyl or##STR131## R⁸ is H, C₁ -C₈ alkyl, C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkyl(C₁ -C₈)alkyl, Ar or Ar--(C₁ -C₈)alkyl; or a pharmaceutically acceptableaddition salt or solvate thereof.
 2. A compound of claim 1 having thestructural formula ##STR132## wherein

    ______________________________________    R          R.sup.1   R.sup.2  R.sup.3                                       X   Y    ______________________________________    H          --CH.sub.3                         --CH.sub.3                                  H    O   --CO.sub.2 C.sub.2 H.sub.5    H          --CH.sub.2 CH.sub.2 --                              H      O   --CO.sub.2 C.sub.2 H.sub.5    H          --(CH.sub.2).sub.4 --                              H      O   --CO.sub.2 C.sub.2 H.sub.5    H          --CH.sub.3                         --CH.sub.3                                  H    O   --CO.sub.2 H    C.sub.6 H.sub.5 CH.sub.2 OC(O)--               --CH.sub.3                         --CH.sub.3                                  H    O   --CO.sub.2 C.sub.2 H.sub.5    (CH.sub.3).sub.3 COC(O)--               --CH.sub.3                         --CH.sub.3                                  H    O   --CO.sub.2 C.sub.2 H.sub.5    C.sub.6 H.sub.5 CH.sub.2 OC(O)--               --CH.sub.3                         --CH.sub.3                                  H    O   --CO.sub.2 H    H          --(CH.sub.2).sub.4 --                              H      O   --CO.sub.2 H    H          --CH.sub.2 CH.sub.2 --                              H      O   --CO.sub.2 H    H          --CH.sub.2 CH.sub.3                         H        H    O   --CO.sub.2 C.sub.2 H.sub.5    H          --CH.sub.2 CH.sub.3                         H        H    O   --CO.sub.2 C.sub.2 H.sub.5    C.sub.6 H.sub.5 CH.sub.2 --               --CH.sub.3                         H        H    O   --CO.sub.2 C.sub.2 H.sub.5               (2,5-cis)    C.sub.6 H.sub.5 CH.sub.2 --               --CH.sub.3                         H        H    O   --CO.sub.2 C.sub.2 H.sub.5               (2,5-               trans)    H          --CH.sub.2 CH.sub.3                         --CH.sub.2 OH                                  H    O   --CO.sub.2 C.sub.2 H.sub.5    H          --CH.sub.2 CH.sub.3                         --CH.sub.2 OH                                  H    O   --CO.sub.2 H    C.sub.6 H.sub.5 CH.sub.2 --               --CH.sub.3                         H        H    O   --CO.sub.2 H               (2,5-cis)    C.sub.6 H.sub.5 CH.sub.2 --               --CH.sub.3                         H        H    O   --CO.sub.2 H               (2,5-               trans)    H          --CH.sub.3                         H        H    S   --CO.sub.2 H               (2,5-cis)    H          --CH.sub.3                         H        H    S   --CO.sub.2 H               (2,5-               trans)    H          --CH.sub.3                         H        H    O   --CO.sub.2 H               (2,5-cis)    H          --CH.sub.3                         H        H    O   --CO.sub.2 H               (2,5-cis)    H          --CH.sub.3                         H        H    O   --CO.sub.2 H               (2,5-               trans)    H          --CH.sub.3                         H        H    S   --CO.sub.2 CH.sub.3               (2,5-cis)    H          --CH.sub.3                         H        H    S   --CO.sub.2 CH.sub.3               (2,5-               trans)    H          H         H        CH.sub.3                                       S   --CO.sub.2 H    H          --CH.sub.2 CH.sub.3                         H        H    O   --CO.sub.2 H               (2,5-cis)    H          --CH.sub.2 CH.sub.3                         H        H    O   --CO.sub.2 H               (2,5-               trans)    C.sub.6 H.sub.5 CH.sub.2 --               H         H        H    O                                           1 #STR133##    H          --(CH.sub.2).sub.4 --                              H      O                                         1 #STR134##    H          CH.sub.3  CH.sub.3 H    O                                           1 #STR135##    H          CH.sub.3  --CH.sub.2 OH                                  H    O   --CO.sub.2 H    H          H         H        H    O                                           1 #STR136##    H          CH.sub.3  --CH.sub.2 OH                                  H    O   --CO.sub.2 C.sub.2 H.sub.5.    ______________________________________


3. A compound of claim 1 wherein R¹ is selected from the groupconsisting of C₁ -C₈ alkyl and hydroxy(C₁ -C₈)alkyl; andR¹ alsorepresents H where:(a) X is S; or (b) Y is --SO₃ H, --SO₂ H, --SO₃ R⁶,--SO₂ NHR⁷, or a group of the formula ##STR137##
 4. A compound of claim3 wherein R³ is H and Y is --CO₂ H, --CO₂ R⁶, --C(O)NHR⁷, or--C(O)--N(OH)--R⁸.
 5. A compound of claim 4 wherein R³ is H, and R¹ andR² are independently selected from H, --CH₃, --C₂ H₅ or --CH₂ OH.
 6. Acompound of claim 4 wherein R³ is H, and R¹ and R2, together with thecarbon atom to which they are attached, comprise a 3-8 memberedcarbocyclic spiro ring, which ring is optionally substituted by an --OHgroup.
 7. A pharmaceutical composition comprising an effective amount ofa compound of claim 1 in combination with a pharmaceutically acceptablecarrier.
 8. A compound of having the structural formula
 9. A compound ofclaim 8 which is a single enantiomer, the hydrochloride salt of whichhas a (+) optical rotation as measured in methanolic or aqueous solutionat room temperature.
 10. A compound selected from the group consistingof: